This invention relates to a synthetic quinolone antibacterial agent which is useful as a medicament, an animal drug, a drug for fishery use and an antibacterial preservative.
That is, the invention relates to a synthetic quinolone antibacterial agent in which the structure of a substituent at the 7-position of the quinolone mother skeleton or a corresponding position (e.g., the 7-position of the 1,4-dihydro-4-oxoquinoline skeleton; the 10-position of 2,3-dihydro-7-oxo-7H-pyrido[1,2,3-de][1.4]benzoxazine skeleton or the like) exerts important influence upon the antibacterial activity, namely a quinolone derivative having a 3-[1-amino-1-aromatic group-substituted]methylpyrrolidin-1-yl group as a substituent which can provide excellent antibacterial activity, and to an antibacterial agent and an antibacterial pharmaceutical preparation, which contain the compound.
It further relates to a synthetic quinolone antibacterial drug, namely a 3-[1-amino-1-aromatic group-substituted]methylpyrrolidine, which has a structure that can provide excellent antibacterial activity and is useful as a production intermediate, and to a protected compound thereof.
Since the discovery of norfloxacin, antibacterial activity and pharmacokinetics of synthetic quinolone antibacterial agents have been sharply improved, and many compounds are now used in the clinical field as chemotherapeutic agents which are effective in almost systemic infectious diseases.
In recent years, generation of bacteria having low sensitivity to synthetic quinolone antibacterial agents has been increasing in the field of clinics. For example, like the case of Staphylococcus aureus (MRSA) and pneumococcus (PRSP) which are non-sensitive to xcex2-lactam antibiotics and enterococcus (VRE) which is non-sensitive to aminoglycoside antibacterial agents, a case has been increasing in which a Gram-positive bacterium originally resistant to drugs other than synthetic quinolone antibacterial agents also became low-sensitive to synthetic quinolone antibacterial agents. In consequence, development of a drug having further high efficacy has been called for in the field of clinics.
Also, a side effect in which convulsions are induced when a non-steroidal anti-inflammatory drug is simultaneously used, as well as other side effects such as phototoxicity and the like, have been revealed, so that development of a synthetic quinolone antibacterial agent having further high safety has also been called for in the field.
It is known that structures of substituents at the 7-position and 1-position are greatly concerned in the antibacterial activity, pharmacokinetics and safety of synthetic quinolone antibacterial agents. It is already known that a quinolone derivative having 3-(aminomethyl)pyrrolidinyl group as the 7-position substituent shows strong antibacterial activity for Gram-negative and Gram-positive bacteria. For example, there is a 7-[3-(aminomethyl)pyrrolidin-1-yl)quinolonecarboxylic acid derivative [Journal of Medicinal Chemistry, vol. 29, p. 445 (1986)]. Also, a 7-[3-(1-aminomethyl)pyrrolidin-1-yl]quinolonecarboxylic acid derivative [Journal of Medicinal Chemistry, vol. 36, p. 871 (1993)], a 7-[3-(1-amino-1-methylethyl)pyrrolidin-1-yl]quinolonecarboxylic acid derivative [Journal of Medicinal Chemistry, vol. 37, p. 733 (1994)], a 7-[3-(1-aminoalkyl)pyrrolidin-1-yl]quinolonecarboxylic acid derivative [Chemical and Pharmaceutical Bulletin, vol. 42, p. 1442 (1994)] and the like are known as quinolonecarboxylic acid derivatives having a substituent on the aminomethyl group of 3-(aminomethyl)pyrrolidin-1-yl group.
However, substituents on the aminomethyl group of currently known 3-(aminomethyl)pyrrolidin-1-yl group are only alkyl groups, and a quinolone compound having an aromatic group as a substituent, which is related to the present invention, is not known.
Also, as a reference in which quinolonecarboxylic acid derivatives having a cyclic substituent on the aminomethyl group of 3-(aminomethyl)pyrrolidin-1-yl group are exemplified, there is, for example, JP-W-3-502452 (the term xe2x80x9cJP-Wxe2x80x9d as used herein means an xe2x80x9cunexamined published Japanese international patent applicationxe2x80x9d), and it describes compounds represented by two general formulae shown below. However, the cyclic substituent on the aminomethyl group of 3-(aminomethyl)pyrrolidin-1-yl group described in this document is limited to a cyclic alkyl, and there is no disclosure on the 3-[1-amino-1-aromatic group-substituted]methylpyrrolidin-1-yl group related to the invention. 
[In the above formula, R12 is an alkyl group having from 1 to 4 carbon atoms, a vinyl group, a haloalkyl group, a hydroxyalkyl group having from 2 to 4 carbon atoms, a cycloalkyl group having from 3 to 6 carbon atoms, phenyl group or a phenyl group substituted with a halogen, an alkyl group, NH2 or OH, R14 is a straight, branched or cyclic lower alkyl group having from 1 to 3 carbon atoms, and X3 is CH, CF, CCl, CBr, N, CCF3, CNH2, CNO2, CR or CORxe2x80x2 (in these formulae, R is a lower alkyl group and Rxe2x80x2 is hydrogen atom or a lower alkyl group).]
In the above formula, Z is 
(wherein m is an integer of from 0 to 4, and R15 and R16 are each independently a hydrogen atom, a lower alkyl group or a cycloalkyl group). In this connection, the definitions of substituents and the like in the above two general formulae are unrelated to those of the compound of the invention, even if the same symbols are used.
In addition, JP-W-9-503783 discloses 2-pyridone carboxylic acid derivatives of 4H-4-oxoquinolizone skeleton and the like shown by the following formula. However, the quinolone compound of the invention having an aromatic substituent on the aminomethyl group moiety of 3-(aminomethyl)pyrrolidin-1-yl group related to the invention is not also exemplified in this document. 
In view of the above, the inventors of the present application have conducted intensive studies with the aim of obtaining excellent quinolone compounds. As a result, it has been found absolutely unexpectedly that an aromatic group-substituted aminomethylpyrrolidine derivative represented by the formula (I) described below, its salts and hydrates thereof can show potent antibacterial activity upon a broad range of Gram-negative and Gram-positive bacteria including drug-resistant bacteria, thereby resulting in the accomplishment of the invention.
The inventors have found that a compound represented by the formula (I) in which an aromatic group-substituted aminomethylpyrrolidine derivatives is introduced onto the 10-position of 2,3-dihydro-3-(S)-methyl-7-oxo-7H-pyrido[1,2,3-de][1.4]benzoxazine skeleton or the 7-position of 6-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-4-oxoquinoline skeleton, its salts and hydrates thereof, having excellent safety, can show broad and excellent antibacterial activity upon any one of Gram-negative and Gram-positive bacteria. At the same time, it was found that it can exert potent antibacterial activity upon drug-resistant Gram-positive bacteria including MRSA, PRSP and VRE, which was not expected before the invention.
Accordingly, the invention relates to a compound represented by the following formula (I), its salts and hydrates thereof 
(wherein R1 represents an aryl group having from 6 to 10 carbon atoms or a heteroaryl group,
wherein the heteroaryl group may be a five-membered ring or a six-membered ring and may contain from 1 to 4 hetero atoms optionally selected from nitrogen atom, oxygen atom and sulfur atom,
wherein these aryl group and heteroaryl group may have one or more substituents selected from the group consisting of an alkyl group having from 1 to 6 carbon atoms, a halogen atom, hydroxyl group, thiol group, amino group, nitro group, cyano group, carboxyl group, carbamoyl group, phenyl group, an alkoxyl group having from 1 to 6 carbon atoms, an alkylthio group having from 1 to 6 carbon atoms, an alkoxycarbonyl group having from 2 to 6 carbon atoms, an acyl group having from 2 to 5 carbon atoms and a heteroaryl group (this heteroaryl group may be a five-membered ring or a six-membered ring and may contain from 1 to 4 hetero atoms optionally selected from nitrogen atom, oxygen atom and sulfur atom),
wherein the alkyl group, alkoxyl group, alkylthio group, alkoxycarbonyl group, acyl group, phenyl group and heteroaryl group among them may have one or more substituents selected from the group consisting of a halogen atom, hydroxyl group, an alkoxyl group having from 1 to 6 carbon atoms and an alkylthio group having from 1 to 6 carbon atoms, and
the amino group may have one or two substituents selected from the group consisting of formyl group, an alkyl group having from 1 to 6 carbon atoms, an acyl group having from 2 to 5 carbon atoms and an alkoxycarbonyl group having from 2 to 5 carbon atoms, R2 and R3 each independently represents hydrogen atom or an alkyl group having from 1 to 6 carbon atoms,
wherein the alkyl group may have one or more substituents selected from the group consisting of hydroxyl group, a halogen atom, an alkylthio group having from 1 to 6 carbon atoms and an alkoxyl group having from 1 to 6 carbon atoms, R4, R5 and R6 each independently represents hydrogen atom, hydroxyl group, a halogen atom, carbamoyl group, an alkyl group having from 1 to 6 carbon atoms, an alkoxy group having from 1 to 6 carbon atoms or an alkylthio group having from 1 to 6 carbon atoms,
wherein the alkyl group among them may have one or more substituents selected from the groups consisting of hydroxyl group, a halogen atom and an alkoxyl group having from 1 to 6 carbon atoms, R7 and R8 each independently represents hydrogen atom or an alkyl group having from 1 to 6 carbon atoms, Q represents a partial structure represented by the following formula 
xe2x80x83[wherein R9 represents an alkyl group having from 1 to 6 carbon atoms, an alkenyl group having from 2 to 6 carbon atoms, a halogenoalkyl group having from 1 to 6 carbon atoms, a cyclic alkyl group having from 3 to 6 carbon atoms which may have a substituent, an aryl group which may have a substituent, a heteroaryl group which may have a substituent, an alkoxyl group having from 1 to 6 carbon atoms or an alkylamino group having from 1 to 6 carbon atoms, R10 represents a hydrogen atom or an alkylthio group having 1 to 6 carbon atoms,
wherein R10 and the aforementioned R9 may be integrated to form a ring structure by incorporating a part of the mother skeleton, and the thus formed ring may contain a sulfur atom as a ring-constituent atom, and the ring may also have an alkyl group having from 1 to 6 carbon atoms as a substituent, R11 represents a hydrogen atom, an amino group, a hydroxyl group, a thiol group, a halogenomethyl group, an alkyl group having from 1 to 6 carbon atoms, an alkenyl group having from 2 to 6 carbon atoms, an alkynyl group having from 2 to 6 carbon atoms or an alkoxyl group having 1 to 6 carbon atoms,
wherein the amino group may have one or two substituents selected from the group consisting of formyl group, an alkyl group having from 1 to 6 carbon atoms and an acyl group having from 2 to 6 carbon atoms,
when R11 is amino group, hydroxyl group or thiol group, they may be protected with a protective group, X1 represents a halogen atom or a hydrogen atom, A1 represents nitrogen atom or a partial structure represented by a formula (II) 
xe2x80x83[wherein X2 represents a hydrogen atom, an amino group, a halogen atom, a cyano group, a halogenomethyl group, a halogenomethoxyl group, an alkyl group having from 1 to 6 carbon atoms, an alkenyl group having from 2 to 6 carbon atoms, an alkynyl group having from 2 to 6 carbon atoms or an alkoxyl group having from 1 to 6 carbon atoms,
wherein the amino group among them may have one or two substituents selected from the group consisting of formyl group, an alkyl group having from 1 to 6 carbon atoms and an acyl group having from 2 to 5 carbon atoms, and
X2 and the aforementioned R9 may be integrated to form a ring structure by incorporating a part of the mother skeleton, and the thus formed ring may contain an oxygen atom, a nitrogen atom or a sulfur atom as a ring-constituent atom, and the ring may also have an alkyl group having from 1 to 6 carbon atoms as a substituent], A2 and A3 each independently represents a nitrogen atom or a carbon atom, and A2 and A3 and the carbon atom, to which they are bonded, form a partial structure
 greater than Cxe2x95x90C(xe2x80x94A1xe2x95x90)xe2x80x94N(xe2x80x94R9)xe2x80x94
xe2x80x83or a partial structure
 greater than Nxe2x80x94C(xe2x80x94A1xe2x95x90)xe2x95x90C(xe2x80x94R9)xe2x80x94
xe2x80x83(wherein xe2x80x9c greater than xe2x80x9d means the presence of 2 bonds to the nitrogen atom or carbon atom, the same shall apply hereinafter), and Y represents a hydrogen atom, a phenyl group, an acetoxymethyl group, a pivaloyloxymethyl group, an ethoxycarbonyl group, a choline group, a dimethylaminoethyl group, a 5-indanyl group, a phthalidinyl group, a 5-alkyl-2-oxo-1,3-dioxol-4-ylmethyl group, a 3-acetoxy-2-oxobutyl group, an alkyl group having from 1 to 6 carbon atoms, an alkoxymethyl group having from 2 to 7 carbon atoms or a phenylalkyl group (composed of an alkylene group having from 1 to 6 carbon atoms and a phenyl group)]}.
The invention also relates to a compound of the formula (I), its salts or hydrates thereof, wherein Q in the formula (I) has a structure represented by formula: 
or formula: 
(wherein A1, R9, R10, R11, X1 and Y are as defined in the foregoing); a compound of the formula (I), its salts or hydrates thereof, wherein Q in the formula (I) has a structure represented by formula: 
(wherein A1, R9, R10, R11, X1 and Y are as defined in the foregoing); a compound of the formula (I), its salts or hydrates thereof, wherein Q in the formula (I) is 6-carboxy-9-fluoro-2,3-dihydro-3-(S)-methyl-7-oxo-7H-pyrido[1,2,3-de][1.4]benzoxazin-10-yl group; [this is represented by the following formula]: 
a compound of the formula (I), its salts or hydrates thereof, wherein Q in the formula (I) is 8-amino-6-carboxy-9-fluoro-2,3-dihydro-3-(S)-methyl-7-oxo-7H-pyrido[1,2,3-de][1.4]benzoxazin-10-yl group; [this is represented by the following formula]: 
a compound of the formula (I), its salts or hydrates thereof, wherein Q in the formula (I) is 3-carboxy-6-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-4-oxo-1,8-naphthyridin-7-yl group; [this is represented by the following formula]: 
a compound of the formula (I), its salts or hydrates thereof, wherein Q in the formula (I) is 3-carboxy-8-chloro-6-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-4-oxoquinolin-7-yl group; [this is represented by the following formula]: 
a compound of the formula (I), its salts or hydrates thereof, wherein Q in the formula (I) is 3-carboxy-6-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-8-methoxy-1,4-dihydro-4-oxoquinolin-7-yl group; [this is represented by the following formula]: 
a compound of the formula (I), its salts or hydrates thereof, wherein Q in the formula (I) is 3-carboxy-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-8-methoxy-1,4-dihydro-4-oxoquinolin-7-yl group; [this is represented by the following formula]: 
a compound of the formula (I), its salts or hydrates thereof, wherein Q in the formula (I) is 3-carboxy-6-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-8-difluoromethoxy-1,4-dihydro-4-oxoquinolin-7-yl group; [this is represented by the following formula]: 
a compound of the formula (I), its salts or hydrates thereof, wherein Q in the formula (I) is 3-carboxy-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-8-difluoromethoxy-1,4-dihydro-4-oxoquinolin-7-yl group; [this is represented by the following formula]: 
a compound of the formula (I), its salts or hydrates thereof, wherein Q in the formula (I) is 3-carboxy-6-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-8-methyl-1,4-dihydro-4-oxoquinolin-7-yl group; [this is represented by the following formula]: 
a compound of the formula (I), its salts or hydrates thereof, wherein Q in the formula (I) is 5-amino-3-carboxy-6-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-8-methoxy-1,4-dihydro-4-oxoquinolin-7-yl group; [this is represented by the following formula]: 
a compound of the formula (I), its salts or hydrates thereof, wherein Q in the formula (I) is 5-amino-3-carboxy-6-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-8-methyl-1,4-dihydro-4-oxoquinolin-7-yl group; [this is represented by the following formula]: 
a compound of the formula (I), its salts or hydrates thereof, wherein Q in the formula (I) is 5-amino-3-carboxy-6,8-difluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-4-oxoquinolin-7-yl group; [this is represented by the following formula]: 
a compound of the formula (I), its salts or hydrates thereof, wherein R1 in the formula (I) is an aryl group having from 6 to 10 carbon atoms which may have a substituent;
a compound of the formula (I), its salts or hydrates thereof, wherein R1 in the formula (I) is an aryl group having from 6 to 10 carbon atoms which may have a substituent, and its aryl group moiety is phenyl group or naphthyl group;
a compound of the formula (I), its salts or hydrates thereof, wherein R1 in the formula (I) is a heteroaryl group which may have a substituent;
a compound of the formula (I), its salt thereof or a hydrate thereof, wherein R1 in the formula (I) is a heteroaryl group which may have a substituent, and its heteroaryl group moiety is furyl group, thienyl group, pyrrolyl group, oxazolyl group, isoxazolyl group, thiazolyl group, isothiazolyl group, imidazolyl group, pyrazolyl group, furazanyl group, pyridyl group, pyrazinyl group, pyrimidyl group, pyridazinyl group, triazinyl group or tetrazinyl group;
a compound of the formula (I), its salts or hydrates thereof, wherein the compound of formula (I) is a stereochemically pure compound;
a compound of the formula (I), its salts or hydrates thereof, wherein R9 is a cyclopropyl group having a halogen atom as a substituent;
a compound of the formula (I), its salts or hydrates thereof, wherein the cyclopropyl group having a halogen atom as a substituent is a 1,2-cis-halogenocyclopropyl group;
a compound of the formula (I), its salts or hydrates thereof, wherein the cyclopropyl group having a halogen atom as a substituent is a stereochemically pure substituent;
a compound of the formula (I), its salts or hydrates thereof, wherein the cyclopropyl group having a halogen atom as a substituent is a (1R,2S)-2-halogenocyclopropyl group;
a compound of the formula (I), its salts or hydrates thereof, wherein halogen atom of the cyclopropyl group having a halogen atom as a substituent is fluorine atom;
a compound of the formula (I), its salts or hydrates thereof, wherein each of R4, R5, R6, R7 and R8 in the formula (I) is hydrogen atom;
a compound of the formula (I), its salts or hydrates thereof, wherein R1 in the formula (I) is an aryl group having from 6 to 10 carbon atoms which may have a substituent or a heteroaryl group of five-membered ring or six-membered ring which contains from 1 to 4 hetero atoms optionally selected from nitrogen atom, oxygen atom and sulfur atom and may have a substituent;
a compound of the formula (I), its salts or hydrates thereof, wherein R1 is phenyl group or naphthyl group;
a compound of the formula (I), its salts or hydrates thereof, wherein R1 is furyl group, thienyl group, pyrrolyl group, oxazolyl group, isoxazolyl group, thiazolyl group, isothiazolyl group, imidazolyl group, pyrazolyl group, furazanyl group, pyridyl group, pyrazinyl group, pyrimidyl group, pyridazinyl group, triazinyl group or tetrazinyl group;
a medicament which comprises a compound of formula (I), its salts or hydrates thereof as an active ingredient;
an antibacterial agent which comprises a compound of formula (I), its salts or hydrates thereof as an active ingredient;
a therapeutic agent for an infectious disease, which comprises a compound of formula (I), its salts or hydrates thereof as an active ingredient;
a method for treating a disease, which comprises administering a compound of formula (I), its salts or hydrates thereof;
a method for treating an infectious disease, which comprises administering a compound of formula (I), its salts or hydrates thereof;
a method for producing a medicament, which comprises formulating a compound of formula (I), its salts or hydrates thereof as an active ingredient;
a method for producing an antibacterial agent, which comprises formulating a compound of formula (I), its salts or hydrates thereof as an active ingredient;
a method for producing an infectious disease treating agent, which comprises formulating a compound of formula (I), its salts or hydrates thereof as an active ingredient;
use of a compound of formula (I), its salts or hydrates thereof in producing a medicament;
use of a compound of formula (I), its salts or hydrates thereof in producing an antibacterial agent;
use of a compound of formula (I), its salts or hydrates thereof in producing an infectious disease treating agent; and so on.
The invention also relates to each of the following items. That is, a compound represented by the following formula, its salts and hydrates thereof 
[wherein R1 represents an aryl group having from 6 to 10 carbon atoms or a heteroaryl group,
wherein the heteroaryl group may be a five-membered ring or a six-membered ring and may contain from 1 to 4 hetero atoms optionally selected from nitrogen atom, oxygen atom and sulfur atom,
wherein these aryl group and heteroaryl group may have one or more substituents selected from the group consisting of a halogen atom, hydroxyl group, thiol group, amino group, nitro group, cyano group, carboxyl group, carbamoyl group, phenyl group, an alkyl group having from 1 to 6 carbon atoms, an alkoxyl group having from 1 to 6 carbon atoms, an alkylthio group having from 1 to 6 carbon atoms, an alkoxycarbonyl group having from 2 to 6 carbon atoms, an acyl group having from 2 to 5 carbon atoms and a heteroaryl group (this heteroaryl group may be a five-membered ring or a six-membered ring and contain from 1 to 4 hetero atoms optionally selected from nitrogen atom, oxygen atom and sulfur atom),
wherein the alkyl group, alkoxyl group, alkylthio group, alkoxycarbonyl group, acyl group, phenyl group and heteroaryl group among them may have one or more substituents selected from the group consisting of a halogen atom, hydroxyl group, an alkoxyl group having from 1 to 6 carbon atoms and an alkylthio group having from 1 to 6 carbon atoms, and
the amino group may have one or two substituents selected from the group consisting of formyl group, an alkyl group having from 1 to 6 carbon atoms, an acyl group having from 2 to 5 carbon atoms and an alkoxycarbonyl group having from 2 to 5 carbon atoms, R222 represents hydrogen atom, an alkyl group having from 1 to 6 carbon atoms or a protective group of an amino group, R3 represents hydrogen atom or an alkyl group having from 1 to 6 carbon atoms,
wherein the alkyl group of R222 and R3 may have one or more substituents selected from the group consisting of hydroxyl group, a halogen atom, an alkylthio group having from 1 to 6 carbon atoms and an alkoxyl group having from 1 to 6 carbon atoms, R4, R5 and R6 each independently represents hydrogen atom, hydroxyl group, a halogen atom, carbamoyl group, an alkyl group having from 1 to 6 carbon atoms, an alkoxyl group having from 1 to 6 carbon atoms or an alkylthio group having from 1 to 6 carbon atoms,
wherein the alkyl group among them may have one or more substituents selected from the group consisting of hydroxyl group, a halogen atom and an alkoxyl group having from 1 to 6 carbon atoms, R7 and R8 each independently represents hydrogen atom or an alkyl group having from 1 to 6 carbon atoms, and Qxe2x80x2 represents a protective group of an amino group];
the compound of the above formula, its salts or hydrates thereof, wherein the protective group of an amino group is a protective group selected from group consisting of an alkoxycarbonyl group which may have a substituent, an aralkyloxycarbonyl group which may have a substituent, an acyl group which may have a substituent, an alkyl group which may have a substituent, an aralkyl group which may have a substituent and substituted silyl groups;
the compound of the above formula, its salts or hydrates thereof, wherein the protective group of an amino group is a protective group selected from the group consisting of tert-butoxycarbonyl group, 2,2,2-trichloroethoxycarbonyl group and the like alkoxycarbonyl groups; benzyloxycarbonyl group, para-methoxybenzyloxycarbonyl group, para-nitrobenzyloxycarbonyl group and the like aralkyloxycarbonyl groups; acetyl group, methoxyacetyl group, trifluoroacetyl group, chloroacetyl group, pivaloyl group, formyl group, benzoyl group and the like acyl groups; tert-butyl group, benzyl group, para-nitrobenzyl group, para-methoxybenzyl group, triphenylmethyl group and the like alkyl groups or aralkyl groups; methoxymethyl group, tert-butoxymethyl group, tetrahydropyranyl group, 2,2,2-trichloroethoxymethyl group and the like ethers; and trimethylsilyl group, isopropyldimethylsilyl group, tert-butyldimethylsilyl group, tribenzylsilyl group, tert-butyldiphenylsilyl group and the like substituted silyl groups;
the compound of the above formula, its salts or hydrates thereof, wherein R222 and Qxe2x80x2 are not the same;
the compound of the above formula, its salts or hydrates thereof, wherein R1 is an aryl group having from 6 to 10 carbon atoms which may have a substituent;
the compound of the above formula, its salts or hydrates thereof, wherein R1 is an aryl group having from 6 to 10 carbon atoms which may have a substituent, and its aryl group moiety is phenyl group or naphthyl group;
the compound of the above formula, its salts or hydrates thereof, wherein R1 is a heteroaryl group which may have a substituent;
the compound of the above formula, its salts or hydrates thereof, wherein R1 is a heteroaryl group which may have a substituent, and its heteroaryl group moiety is furyl group, thienyl group, pyrrolyl group, oxazolyl group, isoxazolyl group, thiazolyl group, isothiazolyl group, imidazolyl group, pyrazolyl group, furazanyl group, pyridyl group, pyrazinyl group, pyrimidyl group, pyridazinyl group, triazinyl group or tetrazinyl group;
the compound of the above formula, its salts or hydrates thereof, wherein the each of R4, R5, R6, R7 and R8 is hydrogen atom; and so on.
The invention also relates to each of the following items. That is, a compound represented by the following formula, its salts and hydrates thereof 
[wherein R1 represents an aryl group having from 6 to 10 carbon atoms or a heteroaryl group,
wherein the heteroaryl group may be a five-membered ring or a six-membered ring and may contain from 1 to 4 hetero atoms optionally selected from nitrogen atom, oxygen atom and sulfur atom,
wherein these aryl group and heteroaryl group may have one or more substituents selected from the group consisting of a halogen atom, hydroxyl group, thiol group, amino group, nitro group, cyano group, carboxyl group, carbamoyl group, phenyl group, an alkyl group having from 1 to 6 carbon atoms, an alkoxyl group having from 1 to 6 carbon atoms, an alkylthio group having from 1 to 6 carbon atoms, an alkoxycarbonyl group having from 2 to 6 carbon atoms, an acyl group having from 2 to 5 carbon atoms and a heteroaryl group (this heteroaryl group may be a five-membered ring or a six-membered ring and contain from 1 to 4 hetero atoms optionally selected from nitrogen atom, oxygen atom and sulfur atom),
wherein the alkyl group, alkoxyl group, alkylthio group, alkoxycarbonyl group, acyl group, phenyl group and heteroaryl group among them may have one or more substituents selected from the group consisting of a halogen atom, hydroxyl group, an alkoxyl group having from 1 to 6 carbon atoms and an alkylthio group having from 1 to 6 carbon atoms,
the amino group may have one or two substituents selected from the group consisting of formyl group, an alkyl group having from 1 to 6 carbon atoms, an acyl group having from 2 to 5 carbon atoms and an alkoxycarbonyl group having from 2 to 5 carbon atoms, R222 represents hydrogen atom, an alkyl group having from 1 to 6 carbon atoms or a protective group of an amino group, R3 represents hydrogen atom or an alkyl group having from 1 to 6 carbon atoms,
wherein the alkyl group of R222 and R3 may have one or more substituents selected from the group consisting of hydroxyl group, a halogen atom, an alkylthio group having from 1 to 6 carbon atoms and an alkoxyl group having from 1 to 6 carbon atoms, R4, R5 and R6 each independently represents hydrogen atom, hydroxyl group, a halogen atom, carbamoyl group, an alkyl group having from 1 to 6 carbon atoms, an alkoxyl group having from 1 to 6 carbon atoms or an alkylthio group having from 1 to 6 carbon atoms,
wherein the alkyl group among them may have one or more substituents selected from the group consisting of hydroxyl group, a halogen atom and an alkoxyl group having from 1 to 6 carbon atoms, and R7 and R8 each independently represents hydrogen atom or an alkyl group having from 1 to 6 carbon atoms];
the compound of the above formula, its salts or hydrates thereof, wherein the protective group of an amino group is a protective group selected from group consisting of an alkoxycarbonyl group which may have a substituent, an aralkyloxycarbonyl group which may have a substituent, an acyl group which may have a substituent, an alkyl group which may have a substituent, an aralkyl group which may have a substituent and substituted silyl groups;
the compound of the above formula, its salts or hydrates thereof, wherein the protective group of an amino group is a protective group selected from the group consisting of tert-butoxycarbonyl group, 2,2,2-trichloroethoxycarbonyl group and the like alkoxycarbonyl groups; benzyloxycarbonyl group, para-methoxybenzyloxycarbonyl group, para-nitrobenzyloxycarbonyl group and the like aralkyloxycarbonyl groups; acetyl group, methoxyacetyl group, trifluoroacetyl group, chloroacetyl group, pivaloyl group, formyl group, benzoyl group and the like acyl groups; tert-butyl group, benzyl group, para-nitrobenzyl group, para-methoxybenzyl group, triphenylmethyl group and the like alkyl groups or aralkyl groups; methoxymethyl group, tert-butoxymethyl group, tetrahydropyranyl group, 2,2,2-trichloroethoxymethyl group and the like ethers; and trimethylsilyl group, isopropyldimethylsilyl group, tert-butyldimethylsilyl group, tribenzylsilyl group, tert-butyldiphenylsilyl group and the like silyl groups;
the compound of the above formula, its salts or hydrates thereof, wherein R1 is an aryl group having from 6 to 10 carbon atoms which may have a substituent;
the compound of the above formula, its salts or hydrates thereof, wherein R1 is an aryl group having from 6 to 10 carbon atoms which may have a substituent, and its aryl group moiety is phenyl group or naphthyl group;
the compound of the above formula, its salts or hydrates thereof, wherein R1 is a heteroaryl group which may have a substituent;
the compound of the above formula, its salts or hydrates thereof, wherein R1 is a heteroaryl group which may have a substituent, and its heteroaryl group moiety is furyl group, thienyl group, pyrrolyl group, oxazolyl group, isoxazolyl group, thiazolyl group, isothiazolyl group, imidazolyl group, pyrazolyl group, furazanyl group, pyridyl group, pyrazinyl group, pyrimidyl group, pyridazinyl group, triazinyl group or tetrazinyl group;
the compound of the above formula, its salts or hydrates thereof, wherein the each of R4, R5, R6, R7 and R8 is hydrogen atom; and so on.
The invention also relates to a method for producing a quinolone compound, which comprises removing Qxe2x80x2 from a compound represented by the following formula, its salts and hydrates thereof 
[wherein R1 represents an aryl group having from 6 to 10 carbon atoms or a heteroaryl group,
wherein the heteroaryl group may be a five-membered ring or a six-membered ring and may contain from 1 to 4 hetero atoms optionally selected from nitrogen atom, oxygen atom and sulfur atom,
wherein these aryl group and heteroaryl group may have one or more substituents selected from the group consisting of a halogen atom, hydroxyl group, thiol group, amino group, nitro group, cyano group, carboxyl group, carbamoyl group, phenyl group, an alkyl group having from 1 to 6 carbon atoms, an alkoxyl group having from 1 to 6 carbon atoms, an alkylthio group having from 1 to 6 carbon atoms, an alkoxycarbonyl group having from 2 to 6 carbon atoms, an acyl group having from 2 to 5 carbon atoms and a heteroaryl group (this heteroaryl group may be a five-membered ring or a six-membered ring and contain from 1 to 4 hetero atoms optionally selected from nitrogen atom, oxygen atom and sulfur atom),
wherein the alkyl group, alkoxyl group, alkylthio group, alkoxycarbonyl group, acyl group, phenyl group and heteroaryl group among them may have one or more substituents selected from the group consisting of a halogen atom, hydroxyl group, an alkoxyl group having from 1 to 6 carbon atoms and an alkylthio group having from 1 to 6 carbon atoms,
the amino group may have one or two substituents selected from the group consisting of formyl group, an alkyl group having from 1 to 6 carbon atoms, an acyl group having from 2 to 5 carbon atoms and an alkoxycarbonyl group having from 2 to 5 carbon atoms, R222 represents hydrogen atom, an alkyl group having from 1 to 6 carbon atoms or a protective group of an amino group, R3 represents hydrogen atom or an alkyl group having from 1 to 6 carbon atoms,
wherein the alkyl group of R222 and R3 may have one or more substituents selected from the group consisting of hydroxyl group, a halogen atom, an alkylthio group having from 1 to 6 carbon atoms and an alkoxyl group having from 1 to 6 carbon atoms, R4, R5 and R6 each independently represents hydrogen atom, hydroxyl group, a halogen atom, carbamoyl group, an alkyl group having from 1 to 6 carbon atoms, an alkoxyl group having from 1 to 6 carbon atoms or an alkylthio group having from 1 to 6 carbon atoms,
wherein the alkyl group among them may have one or more substituents selected from the group consisting of hydroxyl group, a halogen atom and an alkoxyl group having from 1 to 6 carbon atoms, R7 and R8 each independently represents hydrogen atom or an alkyl group having from 1 to 6 carbon atoms, and Qxe2x80x2 represents a protective group of an amino group], if necessary, isolating and purifying, and then allowing it to react with a compound of fomula (III): 
xe2x80x83[wherein X1 represents a halogen atom or hydrogen atom, X4 represents a substituent having a function as a leaving group, such as fluorine atom, chlorine atom, bromine atom, a substituted or unsubstituted phenylsulfonyl group or a substituted or unsubstituted alkylsulfonyl group having from 1 to 3 carbon atoms, Y1 represents hydrogen atom, phenyl group, acetoxymethyl group, pivaloyloxymethyl group, ethoxycarbonyl group, choline group, dimethylaminoethyl group, 5-indanyl group, phthalidinyl group, 5-alkyl-2-oxo-1,3-dioxol-4-ylmethyl group, 3-acetoxy-2-oxobutyl group, an alkyl group having from 1 to 6 carbon atoms, an alkoxymethyl group having from 2 to 7 carbon atoms or a phenylalkyl group (composed of an alkylene group having from 1 to 6 carbon atoms and phenyl group), or a boron-containing substituent represented by formula (IV):
B(Y11)Y12 xe2x80x83xe2x80x83(IV) 
(wherein each of Y11 and Y12 represents fluorine atom or an alkylcarbonyloxy group having from 2 to 4 carbon atoms), R9 represents an alkyl group having from 1 to 6 carbon atoms, an alkenyl group having from 2 to 6 carbon atoms, a halogenoalkyl group having from 1 to 6 carbon atoms, a cyclic alkyl group having from 3 to 6 carbon atoms which may have a substituent, an aryl group which may have a substituent, a heteroaryl group which may have a substituent, an alkoxyl group having from 1 to 6 carbon atoms or an alkylamino group having from 1 to 6 carbon atoms, R10 represents hydrogen atom or an alkylthio group having 1 to 6 carbon atoms,
wherein R10 and the aforementioned R9 may be integrated to form a ring structure by incorporating a part of the mother skeleton, and the thus formed ring may contain a sulfur atom as a ring-constituent atom, and the ring may also have an alkyl group having from 1 to 6 carbon atoms as a substituent, R11 represents hydrogen atom, amino group, hydroxyl group, thiol group, a halogenomethyl group, an alkyl group having from 1 to 6 carbon atoms, an alkenyl group having from 2 to 6 carbon atoms, an alkynyl group having from 2 to 6 carbon atoms or an alkoxyl group having 1 to 6 carbon atoms,
wherein the amino group may have one or two substituents selected from the group consisting of formyl group, an alkyl group having from 1 to 6 carbon atoms and an acyl group having from 2 to 6 carbon atoms,
when R11 is amino group, hydroxyl group or thiol group, they may be protected with a protective group, A1 represents nitrogen atom or a partial structure represented by formula (II): 
xe2x80x83[wherein X2 represents hydrogen atom, amino group, a halogen atom, cyano group, a halogenomethyl group, a halogenomethoxyl group, an alkyl group having from 1 to 6 carbon atoms, an alkenyl group having from 2 to 6 carbon atoms, an alkynyl group having from 2 to 6 carbon atoms or an alkoxyl group having from 1 to 6 carbon atoms,
wherein the amino group among them may have one or two substituents selected from the group consisting of formyl group, an alkyl group having from 1 to 6 carbon atoms and an acyl group having from 2 to 5 carbon atoms, and
X2 and the aforementioned R9 may be integrated to form a ring structure by incorporating a part of the mother skeleton, and the thus formed ring may contain an oxygen atom, a nitrogen atom or a sulfur atom as a ring-constituent atom, and the ring may also have an alkyl group having from 1 to 6 carbon atoms as a substituent)], or with a compound represented by formula (V): 
xe2x80x83(wherein X1, X4, R9, R10, R11, A1 and Y are as defined in the foregoing), in the presence of a base and further carrying out deprotection if necessary.
The invention also relates to a method for producing a quinolone compound, which comprises allowing a compound represented by the following formula, its salts and hydrates thereof 
(wherein R1 represents an aryl group having from 6 to 10 carbon atoms or a heteroaryl group,
wherein the heteroaryl group may be a five-membered ring or a six-membered ring and may contain from 1 to 4 hetero atoms optionally selected from nitrogen atom, oxygen atom and sulfur atom,
wherein these aryl group and heteroaryl group may have one or more substituents selected from the group consisting of a halogen atom, hydroxyl group, thiol group, amino group, nitro group, cyano group, carboxyl group, carbamoyl group, phenyl group, an alkyl group having from 1 to 6 carbon atoms, an alkoxyl group having from 1 to 6 carbon atoms, an alkylthio group having from 1 to 6 carbon atoms, an alkoxycarbonyl group having from 2 to 6 carbon atoms, an acyl group having from 2 to 5 carbon atoms and a heteroaryl group (the heteroaryl group may be a five-membered ring or a six-membered ring and contain from 1 to 4 hetero atoms optionally selected from nitrogen atom, oxygen atom and sulfur atom),
wherein the alkyl group, alkoxyl group, alkylthio group, alkoxycarbonyl group, acyl group, phenyl group and heteroaryl group among them may have one or more substituents selected from the group consisting of a halogen atom, hydroxyl group, an alkoxyl group having from 1 to 6 carbon atoms and an alkylthio group having from 1 to 6 carbon atoms,
the amino group may have one or two substituents selected from the group consisting of formyl group, an alkyl group having from 1 to 6 carbon atoms, an acyl group having from 2 to 5 carbon atoms and an alkoxycarbonyl group having from 2 to 5 carbon atoms, R222 represents hydrogen atom, an alkyl group having from 1 to 6 carbon atoms or a protective group of an amino group, R3 represents hydrogen atom or an alkyl group having from 1 to 6 carbon atoms,
wherein the alkyl group of R222 and R3 may have one or more substituents selected from the group consisting of hydroxyl group, a halogen atom, an alkylthio group having from 1 to 6 carbon atoms and an alkoxyl group having from 1 to 6 carbon atoms, R4, R5 and R6 each independently represents hydrogen atom, hydroxyl group, a halogen atom, carbamoyl group, an alkyl group having from 1 to 6 carbon atoms, an alkoxyl group having from 1 to 6 carbon atoms or an alkylthio group having from 1 to 6 carbon atoms,
wherein the alkyl group among them may have one or more substituents selected from the group consisting of hydroxyl group, a halogen atom and an alkoxyl group having from 1 to 6 carbon atoms, and R7 and R8 each independently represents hydrogen atom or an alkyl group having from 1 to 6 carbon atoms) to react with a compound represented by formula (III): 
xe2x80x83[wherein X1 represents a halogen atom or hydrogen atom, X4 represents a substituent having a function as a leaving group, such as fluorine atom, chlorine atom, bromine atom, a substituted or unsubstituted phenylsulfonyl group or a substituted or unsubstituted alkylsulfonyl group having from 1 to 3 carbon atoms, Y1 represents hydrogen atom, phenyl group, acetoxymethyl group, pivaloyloxymethyl group, ethoxycarbonyl group, choline group, dimethylaminoethyl group, 5-indanyl group, phthalidinyl group, 5-alkyl-2-oxo-1,3-dioxol-4-ylmethyl group, 3-acetoxy-3-oxobutyl group, an alkyl group having from 1 to 6 carbon atoms, an alkoxymethyl group having from 2 to 7 carbon atoms or a phenylalkyl group composed of an alkylene group having from 1 to 6 carbon atoms and phenyl group, or a boron-containing substituent represented by formula (IV):
xe2x80x94B(Y11)Y12 xe2x80x83xe2x80x83(IV) 
(wherein each of Y11 and Y12 represents fluorine atom or an alkylcarbonyloxy group having from 2 to 4 carbon atoms), R9 represents an alkyl group having from 1 to 6 carbon atoms, an alkenyl group having from 2 to 6 carbon atoms, a halogenoalkyl group having from 1 to 6 carbon atoms, a cyclic alkyl group having from 3 to 6 carbon atoms which may have a substituent, an aryl group which may have a substituent, a heteroaryl group which may have a substituent, an alkoxyl group having from 1 to 6 carbon atoms or an alkylamino group having from 1 to 6 carbon atoms, R10 represents hydrogen atom or an alkylthio group having 1 to 6 carbon atoms,
wherein R10 and the aforementioned R9 may be integrated to form a ring structure by incorporating a part of the mother skeleton, and the thus formed ring may contain sulfur atom as a ring-constituent atom, and the ring may also have an alkyl group having from 1 to 6 carbon atoms as a substituent, R11 represents hydrogen atom, amino group, hydroxyl group, thiol group, a halogenomethyl group, an alkyl group having from 1 to 6 carbon atoms, an alkenyl group having from 2 to 6 carbon atoms, an alkynyl group having from 2 to 6 carbon atoms or an alkoxyl group having 1 to 6 carbon atoms,
wherein the amino group may have one or two substituents selected from the group consisting of formyl group, an alkyl group having from 1 to 6 carbon atoms and an acyl group having from 2 to 6 carbon atoms,
when R11 is amino group, hydroxyl group or thiol group, they may be protected with a protective group, A1 represents nitrogen atom or a partial structure represented by formula (II): 
xe2x80x83(wherein X2 represents hydrogen atom, amino group, a halogen atom, cyano group, a halogenomethyl group, a halogenomethoxyl group, an alkyl group having from 1 to 6 carbon atoms, an alkenyl group having from 2 to 6 carbon atoms, an alkynyl group having from 2 to 6 carbon atoms or an alkoxyl group having from 1 to 6 carbon atoms,
wherein the amino group among them may have one or two substituents selected from the group consisting of formyl group, an alkyl group having from 1 to 6 carbon atoms and an acyl group having from 2 to 5 carbon atoms, and
X2 and the aforementioned R9 may be integrated to form a ring structure by incorporating a part of the mother skeleton, and the thus formed ring may contain an oxygen atom, a nitrogen atom or sulfur atom as a ring-constituent atom, and the ring may also have an alkyl group having from 1 to 6 carbon atoms as a substituent)], or with a compound represented by formula (V): 
xe2x80x83(wherein X1, X4, R9, R10, R11, A1 and Y are as defined in the foregoing), in the presence of a base and further carrying out deprotection as occasion demands.
(Mode for Carrying Out the Invention)
The substituents of the compound of the invention represented by formula (I) are described.
The substituent R1 is an aromatic group (an aromatic substituent). The compound of the invention is characterized in that an aromatic substituent is present at this position. This aromatic substituent may be either a hydrocarbon group (an aryl group) or a heterocyclic group (a heteroaryl group). In the case of a hydrocarbon group, it may be either monocyclic or bicyclic. In the case of a heterocyclic group, it may also be either monocyclic or bicyclic. In the case of a monocyclic heterocyclic group, it is a five-membered ring or six-membered ring, and in the case of a bicyclic heterocyclic group, it is a benzo-fused ring system or other than that and a 6-5 fused ring system or a 6-6 fused ring system can be exemplified. Also, in the case of the heterocyclic system, the hetero atom to be contained is from 1 to 4 optionally selected from nitrogen atom, oxygen atom and sulfur atom.
That is, the substituent R1 is an aromatic substituent such as an aryl group having from 6 to 10 carbon atoms or a heteroaryl group.
In this case, the heteroaryl group is a five-membered ring or a six-membered ring and may contain from 1 to 4 hetero atoms optionally selected from nitrogen atom, oxygen atom and sulfur atom.
These aryl group and heteroaryl group may have one or more substituents selected from the group consisting of a halogen atom, hydroxyl group, thiol group, amino group, nitro group, cyano group, carboxyl group, carbamoyl group, phenyl group, an alkyl group having from 1 to 6 carbon atoms, an alkoxyl group having from 1 to 6 carbon atoms, an alkylthio group having from 1 to 6 carbon atoms, an alkoxycarbonyl group having from 2 to 6 carbon atoms, an acyl group having from 2 to 5 carbon atoms and a heteroaryl group (a five-membered ring or a six-membered ring, which contains from 1 to 4 hetero atoms optionally selected from nitrogen atom, oxygen atom and sulfur atom).
The alkyl group, alkoxyl group, alkylthio group, alkoxycarbonyl group, acyl group, phenyl group and heteroaryl group as substituents on the aryl group or heteroaryl group may have one or more substituents selected from the group consisting of a halogen atom, hydroxyl group, an alkoxyl group having from 1 to 6 carbon atoms and an alkylthio group having from 1 to 6 carbon atoms.
Also, the amino group may have one or two substituents selected from the group consisting of formyl group, an alkyl group having from 1 to 6 carbon atoms, an acyl group having from 2 to 5 carbon atoms and an alkoxycarbonyl group having from 2 to 5 carbon atoms.
As the aryl group having from 6 to 10 carbon atoms as the aromatic substituent, phenyl group, pentalenyl group, naphthyl group, azulenyl group and the like can be exemplified, of which phenyl group, 1-naphthyl group and 2-naphthyl group are preferred.
As the heteroaryl group of a five-membered ring or a six-membered ring which contains from 1 to 4 hetero atoms optionally selected from nitrogen atom, oxygen atom and sulfur atom, as the aromatic substituent, furyl group, thienyl group, pyrrolyl group, oxazolyl group, isoxazolyl group, thiazolyl group, isothiazolyl group, imidazolyl group, pyrazolyl group, furazanyl group, pyridyl group, pyrazinyl group, pyrimidyl group, pyridazinyl group, triazinyl group, tetrazinyl group and the like can be exemplified. Preferred among them include 2-furyl group, 3-furyl group, 2-thienyl group, 3-thienyl group, 2-oxazolyl group, 2-thiazolyl group, 2-imidazolyl group, 2-pyridyl group, 3-pyridyl group, 4-pyridyl group, 2-pyrazinyl group, 2-pyrimidyl group, 4-pyrimidyl group, 5-pyrimidyl group and 3-pyridazinyl group. As more preferred examples, 2-furyl group, 3-furyl group, 2-thienyl group, 2-oxazolyl group, 2-thiazolyl group, 2-imidazolyl group, 2-pyridyl group and 4-pyridyl group can be cited.
The substituent on the rings of these aryl group and heteroaryl group may be selected from the group consisting of a halogen atom, hydroxyl group, thiol group, amino group, nitro group, cyano group, carboxyl group, carbamoyl group, phenyl group, an alkyl group having from 1 to 6 carbon atoms, an alkoxyl group having from 1 to 6 carbon atoms, an alkylthio group having from 1 to 6 carbon atoms, an alkoxycarbonyl group having from 2 to 6 carbon atoms, an acyl group having from 2 to 5 carbon atoms and a heteroaryl group (this heteroaryl group is a five-membered ring or a six-membered ring, which contains from 1 to 4 hetero atoms optionally selected from nitrogen atom, oxygen atom and sulfur atom). Among these groups, an alkyl group, an alkoxyl group, an alkylthio group, a halogen atom, hydroxyl group, amino group, carbamoyl group, an alkoxycarbonyl group and phenyl group are preferred, and an alkyl group, an alkoxyl group, an alkylthio group, a halogen atom, hydroxyl group and amino group are particularly preferred substituents.
The substituted aryl group and substituted heteroaryl group as a case in which an alkyl group, an alkoxyl group, an alkylthio group, a halogen atom, hydroxyl group and amino group are preferred as the substituents on the ring of the aryl group and heteroaryl group are described.
When the aryl group and heteroaryl group having an alkyl group as a substituent, the alkyl group may be either straight or branched group having from 1 to 6 carbon atoms, and its preferred examples include methyl group, ethyl group, normal propyl group and isopropyl group.
When the alkyl group has a halogen atom as a substituent, the alkyl group may be either straight or branched form having from 1 to 6 carbon atoms, and fluorine atom is desirable as the substituting halogen atom. With regard to the number of fluorine atoms, it may be any one of from mono-substitution to perfluoro substitution. Its examples include monofluoromethyl group, difluoromethyl group, trifluoromethyl group, 2,2,2-trifluoroethyl group and the like.
When the alkyl group further has hydroxyl group as a substituent, the alkyl group may be either straight or branched form having from 1 to 6 carbon atoms. Though the substituting position of hydroxyl group is not particularly limited, it may preferably be substituted on the terminal carbon atom of the alkyl group. As the alkyl group having hydroxyl group, those which have up to 3 carbon atoms are desirable, and hydroxymethyl group, 2-hydroxyethyl group, 2-hydroxypropyl group, 3-hydroxypropyl group and the like are preferable.
When the alkyl group further has an alkoxyl group as a substituent, the alkyl group may be either straight or branched form having from 1 to 6 carbon atoms, and the substituting alkoxyl group may also be either straight or branched form having from 1 to 6 carbon atoms. Though the substituting position of alkoxyl group is not particularly limited, it may preferably be substituted on the terminal carbon atom of the alkyl group. An alkoxymethyl group, an alkoxyethyl group and an alkoxypropyl group are desirable as the alkyl group having an alkoxyl group, and the alkoxyl group may preferably have up to 3 carbon atoms. More preferred examples include methoxymethyl group, ethoxymethyl group and methoxyethyl group.
When the alkyl group further has an alkylthio group as a substituent, the alkyl group may be either straight or branched form having from 1 to 6 carbon atoms, and the substituting alkylthio group may also be either straight or branched form having from 1 to 6 carbon atoms. Though the substituting position of alkylthio group is not particularly limited, it may preferably be substituted on the terminal carbon atom of the alkyl group. An alkylthiomethyl group, an alkylthioethyl group and an alkylthiopropyl group are desirable as the alkyl group having an alkylthio group, and the alkylthio group may preferably have from 1 to 3 carbon atoms. More preferred examples include methylthiomethyl group, ethylthiomethyl group and methylthioethyl group.
In the aforementioned aryl group and heteroaryl group having an xe2x80x9calkyl group which may have a substituentxe2x80x9d as a substituent, the number of the alkyl groups may be any one of from mono-substitution to peralkyl substitution. When two or more alkyl groups are present, they may be the same or different from one another. As the alkyl substitution, mono-, di- or tri-substitution is suitable.
When the aryl group and heteroaryl group have an alkoxyl group as a substituent, this alkoxyl group may be either straight or branched group having from 1 to 6 carbon atoms, and its preferred examples include methoxy group and ethoxy group.
When the alkoxyl group further has a halogen atom as a substituent, the alkoxyl group may be either straight or branched form having from 1 to 6 carbon atoms, and fluorine atom is desirable as the substituting halogen atom. With regard to the number of fluorine atoms, it may be any one of from mono-substitution to perfluoro substitution. Its examples include monofluoromethoxyl group, difluoromethoxyl group, trifluoromethoxyl group, 2,2,2-trifluoroethyl group and the like.
When the alkoxyl group further has hydroxyl group as a substituent, the alkoxyl group may be either straight or branched form having from 1 to 6 carbon atoms. Though the substituting position of hydroxyl group is not particularly limited, it may preferably be substituted on the terminal carbon atom of the alkoxyl group. As the alkoxyl group having hydroxyl group, those which have up to 3 carbon atoms are desirable, and 1-hydroxyethoxyl group, 2-hydroxyethoxyl group, 2-hydroxypropoxyl group, 3-hydroxypropoxyl group and the like are preferable.
When the alkoxyl group further has an alkoxyl group as a substituent, the alkoxyl group may be either straight or branched form having from 1 to 6 carbon atoms, and the substituting alkoxyl group may also be either straight or branched form having from 1 to 6 carbon atoms. Though the substituting position of alkoxyl group is not particularly limited, it may preferably be substituted on the terminal carbon atom of the alkoxyl group. An alkoxymethyl group, an alkoxyethoxyl group is desirable as the alkoxyl group having an alkoxyl group, and the alkoxyl group may preferably have up to 3 carbon atoms. More preferred examples include 2-methoxyethoxyl group and 2-ethoxyethoxyl group.
When the alkoxyl group further has an alkylthio group as a substituent, the alkoxyl group may be either straight or branched form having from 1 to 6 carbon atoms, and the substituting alkylthio group may also be either straight or branched form having from 1 to 6 carbon atoms. Though the substituting position of alkylthio group is not particularly limited, it may preferably be substituted on the terminal carbon atom of the alkoxyl group. An alkylthioethoxyl group is desirable as the alkoxyl group having an alkylthio group, and the alkylthio group may preferably have from 1 to 3 carbon atoms. More preferred examples include 2-methylthioethoxyl group and 2-ethylthioethoxyl group.
In the aforementioned aryl group and heteroaryl group having an xe2x80x9calkoxyl group which may have a substituentxe2x80x9d as a substituent, the number of the alkoxyl groups may be any one of from mono-substitution to peralkoxyl substitution. When two or more alkoxyl groups are present, they may be the same or different from one another. As the alkoxyl substitution, mono-, di- or tri-substitution is suitable.
When the aryl group and heteroaryl group have an alkylthio group as a substituent, the alkylthio group may be either straight or branched group having from 1 to 6 carbon atoms, and its preferred examples include methylthio group and ethylthio group.
When the alkylthio group has a halogen atom as a substituent, the alkylthio group may be either straight or branched form having from 1 to 6 carbon atoms, and fluorine atom is desirable as the halogen atom. With regard to the number of fluorine atoms, it may be any one of from mono-substitution to perfluoro substitution. Its examples include monofluoromethylthio group, difluoromethylthio group, trifluoromethylthio group, 2,2,2-trifluoroethylthio group and the like.
When the alkylthio group further has hydroxyl group as a substituent, the alkylthio group may be either straight or branched form having from 1 to 6 carbon atoms. Though the substituting position of hydroxyl group is not particularly limited, it may preferably be substituted on the terminal carbon atom of the alkylthio group. As the alkylthio group having hydroxyl group, those which have up to 3 carbon atoms are desirable, and hydroxymethylthio group, 1-hydroxyethylthio group, 2-hydroxyethylthio group, 2-hydroxypropylthio group, 3-hydroxypropylthio group and the like are preferable.
When the alkylthio group further has an alkoxyl group as a substituent, the alkylthio group may be either straight or branched form having from 1 to 6 carbon atoms, and the substituting alkoxyl group may also be either straight or branched form having from 1 to 6 carbon atoms. Though the substituting position of alkoxyl group is not particularly limited, it may preferably be substituted on the terminal carbon atom of the alkylthio group. An alkoxyethylthio group, an alkoxyethyl group and an alkoxypropyl group is desirable as the alkylthio group having an alkoxyl group, and the alkoxyl group may preferably have up to 3 carbon atoms. More preferred examples include 2-methoxyethylthio group and 2-ethoxyethylthio group.
When the alkylthio group further has an alkylthio group as a substituent, the alkylthio group may be either straight or branched form having from 1 to 6 carbon atoms, and the substituting alkylthio group may also be either straight or branched form having from 1 to 6 carbon atoms. Though the substituting position of alkylthio group is not particularly limited, it may preferably be substituted on the terminal carbon atom of the alkylthio group. An alkylthioethylthio group is desirable as the alkylthio group having an alkylthio group, and the alkylthio group may preferably have from 1 to 3 carbon atoms. More preferred examples include 2-methylthioethylthio group and 2-ethylthioethylthio group.
In such an aryl group or heteroaryl group having an xe2x80x9calkylthio group which may have a substituentxe2x80x9d as a substituent, the number of the alkylthio groups may be any one of from mono-substitution to peralkylthio substitution. When two or more alkylthio groups are present, they may be the same or different from one another. As the alkylthio substitution, mono-substitution is suitable.
When the aryl group and heteroaryl group have a halogen atom as a substituent, fluorine atom, chlorine atom and bromine atom are desirable as the halogen atom. Fluorine atom is particularly desirable, and the number of fluorine atoms in that case may be any one of from mono-substitution to perfluoro substitution.
Its examples include 2-fluorophenyl group, 3-fluorophenyl group, 4-fluorophenyl group, 2,4-difluorophenyl group, 2,5-difluorophenyl group, 2,6-difluorophenyl group, 3,4-difluorophenyl group, 3,5-difluorophenyl group, 2,4,6-trifluorophenyl group, 3,4,5-trifluorophenyl group, 2,3,5,6-tetrafluorophenyl group, pentafluorophenyl group, 4-fluoro-1-naphthyl group, 7-fluoro-1-naphthyl group, 3-fluoro-2-pyridyl group, 6-fluoro-2-pyridyl group, 2,4,5,6-tetrafluoro-3-pyridyl group, 2,3,5,6-tetrafluoro-4-pyridyl group and the like.
When the aryl group and heteroaryl group have hydroxyl group as a substituent, an aryl group substituted with hydroxyl group is preferred, and a substituted phenyl group is particularly preferred. For example, 2-hydroxyphenyl group, 3-hydroxyphenyl group, 4-hydroxyphenyl group, 2,4-dihydroxyphenyl group and the like can be cited.
When the aryl group and heteroaryl group have amino group as a substituent, an amino-substituted aryl group is preferred, and an amino-substituted phenyl group is particularly preferred. The amino group of this case may have 1 or 2 substituents selected from the group consisting of formyl group, an alkyl group having from 1 to 6 carbon atoms, an acyl group having from 2 to 5 carbon atoms and an alkoxycarbonyl group having from 2 to 5 carbon atoms, and a monoalkylamino-substituted phenyl group, a dialkylamino-substituted phenyl group (the alkyl groups of this case may be the same or different from each other) and an acylamino-substituted phenyl group are preferable.
2-Aminophenyl group, 3-aminophenyl group, 4-aminophenyl group, 2-methylaminophenyl group, 4-methylaminophenyl group, 2-dimethylaminophenyl group, 4-dimethylaminophenyl group, 4-acetoxyaminophenyl group and the like can be exemplified.
When the aryl group and heteroaryl group have two or more substituents, their combination may be a combination optionally selected from the group consisting of a halogen atom, hydroxyl group, thiol group, amino group, nitro group, cyano group, carboxyl group, carbamoyl group, phenyl group, an alkyl group having from 1 to 6 carbon atoms, an alkoxyl group having from 1 to 6 carbon atoms, an alkylthio group having from 1 to 6 carbon atoms, an alkoxycarbonyl group having from 2 to 6 carbon atoms, an acyl group having from 2 to 5 carbon atoms and a heteroaryl group (a five-membered ring or a six-membered ring and contains from 1 to 4 hetero atoms optionally selected from nitrogen atom, oxygen atom and sulfur atom), but it is desirable that one of them is selected from an alkyl group, an alkoxy group, a halogen atom, hydroxyl group and amino group. As the halogen atom, fluorine atom is particularly desirable.
As examples of the case in which the aryl group and heteroaryl group have two or more substituents, 2-fluoro-4-hydroxyphenyl group, 3-amino-4,6-difluorophenyl group, 4,6-difluoro-3-methylaminophenyl group, 2,6-difluoro-4-methoxyphenyl group, 4-fluoro-2-methylphenyl group, 4-hydroxy-3,5-dimethylphenyl group, 3,5-dimethyl-4-methoxyphenyl group, 6-amino-3,5-difluoro-2-pyridyl group, 5-chloro-6-methyl-4-pyrimidinyl group and the like can be cited.
In this connection, the carbon atom, to which R1 is bonded, becomes an asymmetric carbon to generate isomers, and all of such isomers are included in the invention.
Also, when the substituent of R1 is a (substituted) phenyl group or a biaryl type (substituted) heteroaryl group of a five-membered ring or a six-membered ring containing from 1 to 4 hetero atoms optionally selected from nitrogen atom, oxygen atom and sulfur atom (the term xe2x80x9c(substituted)xe2x80x9d means that it may have a substituent), it generates isomers originated from axial chirality, and all of such isomers are included in the invention.
The substituents R2 and R3 each independently represents hydrogen atom or an alkyl group having from 1 to 6 carbon atoms, and the alkyl group may have one or more substituents selected from the group consisting of hydroxyl group, a halogen atom, an alkylthio group having from 1 to 6 carbon atoms and an alkoxyl group having from 1 to 6 carbon atoms.
As the alkyl group, it may be either straight or branched group having from 1 to 6 carbon atoms, and its preferred examples include methyl group, ethyl group, normal propyl group and isopropyl group.
When the alkyl group further has hydroxyl group as a substituent, the alkyl group may be either straight or branched form having from 1 to 6 carbon atoms. Though the substituting position of hydroxyl group is not particularly limited, it may preferably be substituted on the terminal carbon atom of the alkyl group. As the alkyl group having hydroxyl group, those which have up to 3 carbon atoms are desirable, and hydroxymethyl group, 2-hydroxyethyl group, 2-hydroxypropyl group, 3-hydroxypropyl group and the like are preferable.
When the alkyl group further has a halogen atom as a substituent, the alkyl group may be either straight or branched form having from 1 to 6 carbon atoms, and fluorine atom is desirable as the halogen atom. With regard to the number of fluorine atoms, it may be any one of from mono-substitution to perfluoro substitution. Its examples include monofluoromethyl group, difluoromethyl group, trifluoromethyl group, 2,2,2-trifluoroethyl group and the like.
When the alkyl group further has an alkylthio group as a substituent, the alkyl group may be either straight or branched form having from 1 to 6 carbon atoms, and the substituting alkylthio group may also be either straight or branched form having from 1 to 6 carbon atoms. Though the substituting position of alkylthio group is not particularly limited, it may preferably be substituted on the terminal carbon atom of the alkyl group. An alkylthiomethyl group, an alkylthioethyl group and an alkylthiopropyl group are desirable as the alkyl group having an alkylthio group, and the alkylthio group may preferably have from 1 to 3 carbon atoms. More preferred examples include methylthiomethyl group, ethylthiomethyl group and methylthioethyl group.
When the alkyl group further has an alkoxyl group as a substituent, the alkyl group may be either straight or branched form having from 1 to 6 carbon atoms, and the substituting alkoxyl group may also be either straight or branched form having from 1 to 6 carbon atoms. Though the substituting position of alkoxyl group is not particularly limited, it may preferably be substituted on the terminal carbon atom of the alkyl group. An alkoxymethyl group, an alkoxyethyl group and an alkoxypropyl group are desirable as the alkyl group having an alkoxyl group, and the alkoxyl group may preferably have up to 3 carbon atoms. More preferred examples include methoxymethyl group, ethoxymethyl group and methoxyethyl group.
R4, R5 and R6 each independently represents hydrogen atom, hydroxyl group, a halogen atom, carbamoyl group, an alkyl group having from 1 to 6 carbon atoms, an alkoxy group having from 1 to 6 carbon atoms or an alkylthio group having from 1 to 6 carbon atoms, and the alkyl group among them may have one or more substituents selected from the group consisting of hydroxyl group, a halogen atom and an alkoxyl group having from 1 to 6 carbon atoms. In addition, R5 and R6 integrated into a polymethylene chain having from 3 to 6 carbon atoms (forms a spiro-ring system together with pyrrolidine ring), hydroxyimino group or an alkyloxyimino group having from 1 to 6 carbon atoms.
As the halogen atom, fluorine atom or chlorine atom is desirable.
As the alkyl group, it may be either straight or branched group having from 1 to 6 carbon atoms, and its preferred examples include methyl group, ethyl group, normal propyl group and isopropyl group.
As the alkoxyl group, it may be either straight or branched group having from 1 to 6 carbon atoms, and its preferred examples include methoxy group and ethoxy group.
As the alkylthio group, it may be either straight or branched group having from 1 to 6 carbon atoms, and its preferred examples include methylthio group and ethylthio group.
When hydroxyl group is present as a substituent on an alkyl group having from 1 to 6 carbon atoms, the alkyl group may be either straight or branched form. Though the substituting position of hydroxyl group is not particularly limited, it may preferably be substituted on the terminal carbon atom of the alkyl group. Preferred examples of the hydroxyl group-substituted alkyl group having from 1 to 6 carbon atoms include hydroxymethyl group, 2-hydroxyethyl group and 3-hydroxypropyl group.
As the halogen atom of an alkyl group having a halogen atom, fluorine and chlorine atoms are preferable, and fluorine atom is particularly preferable. The alkyl group may be either a straight or branched form.
In the alkoxyl group-containing alkyl group having from 1 to 6 carbon atoms, each of the alkyl group moieties may be either a straight or branched form, and an alkoxymethyl group or an alkoxyethyl group is preferable. Methoxymethyl group, ethoxymethyl group and 2-methoxyethyl group can be cited or more preferred examples.
When the substituents R5 and R6 are integrated to form a polymethylene chain, a ring of from three- to six-membered ring is newly added to the pyrrolidine ring to form a spiro-ring structure. As the size of the newly formed ring, a cyclopropyl ring or cyclobutyl ring having 2 or 3 carbon atoms is preferable.
Also, when the substituents R5 and R6 are integrated into an alkyloxyimino group represented by the following formula,
xe2x95x90Nxe2x80x94O-Alkyl 
the alkyl group may be either a straight or branched form. Preferred as the alkyloxyimino group are methoxyimino group and ethoxyimino group.
The substituents R7 and R8 each independently represents hydrogen atom or an alkyl group having from 1 to 6 carbon atoms. As the alkyl group, it may be either a straight or branched group having from 1 to 6 carbon atoms and is preferably methyl group, ethyl group, normal propyl group or isopropyl group. A case in which each of them is hydrogen atom is desirable.
Q is a partial structure represented by the following formula. 
In the structural formula, A2 and A3 each independently represents nitrogen atom or carbon atom, and A2 and A3 and the carbon atoms, to which they are bonded, are linked to form a partial structure
 greater than Cxe2x95x90C(xe2x80x94A1xe2x95x90)xe2x80x94N(xe2x80x94R9)xe2x80x94
or a partial structure
 greater than Nxe2x80x94C(xe2x80x94A1xe2x95x90)xe2x95x90C(xe2x80x94R9)xe2x80x94.
A fused heterocyclic system partial structure represented by the following formula 
or the following formula 
is preferred as the structure of Q.
The substituent R9 is an alkyl group having from 1 to 6 carbon atoms, an alkenyl group having from 2 to 6 carbon atoms, a halogenoalkyl group having from 1 to 6 carbon atoms, a cyclic alkyl group having from 3 to 6 carbon atoms which may have a substituent, an aryl group which may have a substituent, a heteroaryl group which may have a substituent, an alkoxyl group having from 1 to 6 carbon atoms or an alkylamino group having from 1 to 6 carbon atoms.
In this case, ethyl group is particularly desirable as the alkyl group having from 1 to 6 carbon atoms. As the alkenyl group having from 2 to 6 carbon atoms, vinyl group or 1-isopropenyl group is desirable. 2-Fluoroethyl group is desirable as the halogenoalkyl group having from 1 to 6 carbon atoms. Cyclopropyl group is particularly desirable as the cyclic alkyl group, and a halogen atom, particularly fluorine atom, is desirable as the substituent of the cyclic alkyl group.
Examples of the aryl group which may have a substituent include phenyl or the like group which may have 1 to 3 substituents selected from the group consisting, for example, of fluorine atom, chlorine atom, bromine atom or the like halogen atom, hydroxyl group, amino group, nitro group, an alkyl group having from 1 to 6 carbon atoms and an alkoxyl group having from 1 to 6 carbon atoms, and its preferred examples include phenyl group, 2-fluorophenyl group, 4-fluorophenyl group, 2,4-difluorophenyl group, 2-fluoro-4-hydroxyphenyl group, 3-amino-4,6-difluorophenyl group and 4,6-difluoro-3-methylaminophenyl group. This aryl group may be the same as the aryl group of the substituent R1 or different from it.
The heteroaryl group is a compound derived from a five-membered or six-membered aromatic heterocyclic compound which contains one or more hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom. This heteroaryl group may be the same as the heteroaryl group of the substituent R1 or different from it. As the heteroaryl group of the substituent R9, pyridyl group, pyrimidyl group and the like can be exemplified. As the substituent on these rings, an alkyl group, a halogen atom or the like is desirable. Particularly preferred is 6-amino-3,5-difluoro-2-pyridyl group.
Methoxyl group is desirable as the alkoxyl group having from 1 to 6 carbon atoms. Methylamino group is desirable as the alkylamino group having from 1 to 6 carbon atoms.
As the substituent R9, a cyclic alkyl group or a halogenocycloalkyl group is desirable. Among these groups, cyclopropyl group or a 2-halogenocyclopropyl group is desirable. As the halogen atom, fluorine atom is desirable.
The substituent R10 represents hydrogen atom or an alkylthio group having from 1 to 6 carbon atoms, or R9 and R10 may be integrated to form a hydrocarbon system ring structure by incorporating a part of the mother skeleton (namely by including the carbon atom to which R10 is bonded and A2). The thus formed ring may contain sulfur atom as a constituent atom, and the ring may further have an alkyl group having from 1 to 6 carbon atoms as a substituent. The ring to be formed herein may have a size of from four-membered ring to six-membered ring, and the ring may be saturated or unsaturated. As the fused ring structure formed in this manner, the following can be exemplified. 
The substituent X1 is a halogen atom or hydrogen atom, and fluorine atom is desirable in the case of the halogen atom. Among these atoms, fluorine atom or hydrogen atom is desirable as the substituent.
The substituent R11 represents hydrogen atom, amino group, hydroxyl group, thiol group, a halogenomethyl group, an alkyl group having from 1 to 6 carbon atoms, an alkenyl group having from 2 to 6 carbon atoms, an alkynyl group having from 2 to 6 carbon atoms or an alkoxyl group having from 1 to 6 carbon atoms, and the amino group among them may have one or two substituents selected from the group consisting of formyl group, an alkyl group having from 1 to 6 carbon atoms and an acyl group having from 2 to 6 carbon atoms.
As the alkyl group, it may be either a straight or branched group having from 1 to 6 carbon atoms, and its preferred examples include methyl group, ethyl group, normal propyl group and isopropyl group. The alkenyl group may be either a straight or branched group having from 2 to 6 carbon atoms and is preferably vinyl group. As the alkynyl group, it may be either a straight or branched group having from 2 to 6 carbon atoms and is preferably ethynyl group. Fluorine atom is particularly desirable as the halogen of the halogenomethyl group, and its number may be from 1 to 3. The alkoxyl group may have from 1 to 6 carbon atoms and is preferably methoxyl group.
The substituent R11 is preferably hydrogen atom, an alkyl group or amino group, of which methyl group or unsubstituted amino group is preferred.
When the substituent R11 is amino group, hydroxyl group or thiol group, they may be protected with ordinarily used protective groups.
Examples of such protective groups include tert-butoxycarbonyl group, 2,2,2-trichloroethoxycarbonyl group and the like (substituted) alkoxycarbonyl groups; benzyloxycarbonyl group, para-methoxybenzyloxycarbonyl group, para-nitrobenzyloxycarbonyl group and the like (substituted) aralkyloxycarbonyl groups; acetyl group, methoxyacetyl group, trifluoroacetyl group, chloroacetyl group, pivaloyl group, formyl group, benzoyl group and the like (substituted) acyl groups; tert-butyl group, benzyl group, para-nitrobenzyl group, para-methoxybenzyl group, triphenylmethyl group and the like (substituted) alkyl groups or (substituted) aralkyl groups; methoxymethyl group, tert-butoxymethyl group, tetrahydropyranyl group, 2,2,2-trichloroethoxymethyl group and the like (substituted) ethers; and trimethylsilyl group, isopropyldimethylsilyl group, tert-butyldimethylsilyl group, tribenzylsilyl group, tert-butyldiphenylsilyl group and the like (alkyl and or aralkyl)-substituted silyl groups. Compounds having substituents protected with these substituents are particularly desirable as intermediates for the production.
When A1 is a partial structure of the following formula (II), 
X2 represents hydrogen atom, amino group, a halogen atom, cyano group, a halogenomethyl group, a halogenomethoxyl group, an alkyl group having from 1 to 6 carbon atoms, an alkenyl group having from 2 to 6 carbon atoms, an alkynyl group having from 2 to 6 carbon atoms or an alkoxyl group having from 1 to 6 carbon atoms, wherein the amino group may have one or two substituents selected from the group consisting of formyl group, an alkyl group having from 1 to 6 carbon atoms and an acyl group having from 2 to 5 carbon atoms.
As the alkyl group, it may be either a straight or branched group having from 1 to 6 carbon atoms and its preferred examples include methyl group, ethyl group, normal propyl group and isopropyl group. The alkenyl group may be either a straight or branched group having from 2 to 6 carbon atoms and is preferably vinyl group. The alkynyl group may be either a straight or branched group having from 2 to 6 carbon atoms and is preferably ethynyl group. Fluorine atom is particularly desirable as the halogen of the halogenomethyl group, and its number may be from 1 to 3. As the alkoxyl group, it may have from 1 to 6 carbon atoms and is preferably methoxyl group. Fluorine atom is particularly desirable as the halogen of the halogenomethoxyl group, and its number may be from 1 to 3.
Among these substituents, an alkyl group or an alkoxyl group is desirable. More preferred are methyl group and ethyl group. These are desirable substituents particularly when Q is a partial structure shown by the following formula. 
In addition, this X2 and the aforementioned R9 may be integrated to form a hydrocarbon system ring structure (size of the ring may be from four-membered ring to seven-membered ring, and it may be saturated or unsaturated) by incorporating a part of the mother skeleton (namely by including the carbon atom to which X2 is bonded and A2), and the thus formed ring may contain oxygen atom, nitrogen atom or sulfur atom as a constituent atom, and the ring may also have an alkyl group having from 1 to 6 carbon atoms as a substituent. As the fused ring structure formed in this manner, the following can be exemplified. 
Among these fused ring systems, 2,3-dihydro-7-oxo-7H-pyrido[1,2,3-de] [1.4]benzoxazine-6-carboxylic acid-10-yl group, particularly its 3-position (S) -methyl form, is desirable.
As Q, a partial structure of the following formula 
is desirable. Also in this case, it is desirable that A1 is the partial structure of formula (II).
When Q is the partial structure described above and A1 is the partial structure of formula (II), a preferred combination of R11 and X2 is a case in which R11 is amino group, hydrogen atom, hydroxyl group or an alkyl group having from 1 to 6 carbon atoms and X2 is an alkyl group having from 1 to 6 carbon atoms, an alkoxyl group having from 1 to 6 carbon atoms, a halogenomethoxyl group or hydrogen atom.
A more preferred combination is a case in which R11 is amino group, hydrogen atom, hydroxyl group or methyl group and X2 is methyl group, methoxy group, difluoromethoxyl group or hydrogen atom.
A most preferred combination is a case in which R11 is amino group, hydrogen atom, hydroxyl group or methyl group and X2 is methyl group or methoxyl group.
For these R11 and X2, fluorine atom is desirable as X1.
When the substituents X1 and X2 are halogen atoms, fluorine atom is particularly preferable as X1, and fluorine atom or chlorine atom is preferable as X2.
When Q is a partial structure represented by the following formula 
and A1 is the partial structure of formula (II), a preferred combination of R11 and X2 is a case in which R11 is amino group, hydrogen atom, hydroxyl group or an alkyl group having from 1 to 6 carbon atoms and X2 is an alkyl group having from 1 to 6 carbon atoms, an alkoxyl group having from 1 to 6 carbon atoms, a halogenomethoxyl group or hydrogen atom.
A more preferred combination is a case in which R11 is amino group, hydrogen atom, hydroxyl group or methyl group and X2 is methyl group, methoxyl group, difluoromethoxyl group or hydrogen atom.
A most preferred combination is a case in which R11 is amino group, hydrogen atom, hydroxyl group or methyl group and X2 is methyl group or methoxyl group.
When the substituents X1 and X2 are halogen atoms, fluorine atom is particularly preferable as X1, and fluorine atom or chlorine atom is preferable as X2.
Next, the halogenocyclopropyl group of R9 is described.
As the substitutable halogen atom, fluorine atom and chlorine atom can be exemplified, of which fluorine atom is particularly preferred.
Regarding the steric environment at this moiety, it is particularly desirable that the halogen atom and pyridonecarboxylic acid moiety have cis-configuration on the cyclopropane ring.
So-called enantiomeric isomers are present due to the cis-2-halogenocyclopropyl moiety along of R9, and strong antibacterial activity and high safety have been found in both isomers.
The compound of the invention shows excellent characteristics by having a pyrrolidinyl substituent of a structure shown below. 
In this substituent, the above four isomers are present based on the asymmetric carbon atom on the pyrrolidin ring to which the substituent xe2x80x94CH(xe2x80x94R1)N(xe2x80x94R2)xe2x80x94R3 and the substituent R4 are bonded and an asymmetric carbon atom to which R1 is bonded.
On the other hand, structure activity correlation among four optically active substances derived from steric configuration of the 7-position substituent in a 7-[3-(1-aminoethyl)pyrrolidin-1-yl]quinolonecarboxylic acid derivative is described in Chemical and Pharmaceutical Bulletin, vol. 42, p. 1442 (1994). It described that 3-(S)-[1-(R)-aminoethyl]pyrrolidin-1-yl group has the most highest antibacterial activity among the four optically active substances.
The present inventors have considered that 
was most desirable among the four optically active substances having the structures shown in the above.
That is, the compound of the invention is characterized in that the aromatic group-substituted aminomethylpyrrolidine derivative represented by the formula (I), salts thereof and hydrates thereof show broad and potent antibacterial activity upon Gram-negative bacteria and Gram-positive bacteria, and show potent antibacterial activity particularly upon resistant strains of Gram-positive bacteria including MRSA, PRSP and VRE.
Particularly, a compound represented by the formula (I) in which the aromatic group-substituted aminomethylpyrrolidine derivative having the aforementioned structure was introduced at the 10-position of the 2,3-dihydro-3-(S)-methyl-7-oxo-7H-pyrido[1,2,3-de] [1.4]benzoxazine skeleton or the 7-position of the 6-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-4-oxoquin oline skeleton having excellent safety, salts thereof and hydrates thereof showed broad and strong antibacterial activity upon both of Gram-negative bacteria and Gram-positive bacteria including drug resistant strains, which was not expected before the invention.
When a compound of formula (I) of the invention has a structure in which diastereomers are present, and when such a compound of the invention is administered to human and animals, it is desirable to administer a compound which comprises a single diastereomer. The term xe2x80x9ccomprises a single diastereomerxe2x80x9d as used herein means not only a case in which it is completely free from the other diastereomer but also a case in which it is in a chemically pure degree. In other words, it is interpretable that the other diastereomer may be present in such a degree that it does not exert influences upon physical constants and physiological activities of the compound.
Also, the term xe2x80x9cstereochemically purexe2x80x9d as used herein means that, when a compound or the like exists in a plurality of isomer forms due to the presence of asymmetric carbon atoms, the compound is comprised of only one of them. The term xe2x80x9cpurexe2x80x9d in this case can also be considered in the same manner as described above.
The pyridonecarboxylic acid derivative of the invention may be used either in its free form or as an acid addition salt or a salt of its carboxyl group. Examples of the acid addition salt include hydrochloride, sulfate, nitrate, hydrobromide, hydroiodide, phosphate and the like inorganic acid salts, or acetate, methanesulfonate, benzenesulfonate, toluenesulfonate, citrate, maleate, fumarate, lactate and the like organic acid salts.
The salt of carboxyl group may be either an inorganic or an organic salt, and its examples include lithium salt, sodium salt, potassium salt and the like alkali metal salts, magnesium salt, calcium salt and the like alkaline earth metal salts, ammonium salt, or triethylamine salt, N-methylglucamine salt, tris-(hydroxylmethyl)aminomethane salt and the like.
Also, these free form, acid addition salts and salts of carboxyl group of the compound of the invention may be present as hydrates.
On the other hand, a quinolone derivative whose carboxylic acid moiety is an ester is useful as a synthesis intermediate or a prodrug. For example, alkyl esters, benzyl esters, alkoxyalkyl esters, phenylalkyl esters and phenyl esters are useful as synthesis intermediates.
Also, the ester to be used as a prodrug is an ester which is easily hydrolyzed in the living body and forms free form of carboxylic acid, and its examples include acetoxymethyl ester, pivaloyloxymethyl ester, ethoxycarbonyl ester, choline ester, dimethylaminoethyl ester, 5-indanyl ester, phthalidinyl ester, and 5-alkyl-2-oxo-1,3-dioxol-4-ylmethyl ester, 3-acetoxy-2-oxobutyl ester or the like oxoalkyl ester.
The compound of the invention represented by the formula (I) can be produced by various methods, and, in a preferred example, it can be produced for example by allowing a compound represented by formula (III): 
[wherein X4 is a substituent which functions as a leaving group, such as fluorine atom, chlorine atom, bromine atom, substituted or unsubstituted phenylsulfonyl group or a substituted or unsubstituted alkylsulfonyl group having from 1 to 3 carbon atoms, Y1 is the Y defined in the formula (I) or a boron-containing group represented by formula (IV):
xe2x80x94B(Y11)Y12 xe2x80x83xe2x80x83(IV) 
(wherein each of Y11 and Y12 is fluorine atom or an alkylcarbonyloxy group having from 2 to 4 carbon atoms), and R9, R10, R11, A1 and X1 are as defined in the formula (I)], or a compound represented by formula (V): 
[wherein X4 is a substituent which functions as a leaving group, such as fluorine atom, chlorine atom, bromine atom, substituted or unsubstituted phenylsulfonyl group or a substituted or unsubstituted alkylsulfonyl group having from 1 to 3 carbon atoms, and R9, R10, R11, A1, X1 and Y are as defined in the formula (I)] to react with a compound represented by the following formula (VI) 
[wherein R222 is the same as the R2 defined in the formula (I), and R1, R3, R4, R5, R6, R7 and R8 are as defined in the formula (I)] or an addition salt thereof.
The reaction can be carried out using or without using a solvent. The solvent to be used in the reaction may be any solvent which is inert under the reaction conditions, and its examples include dimethyl sulfoxide, pyridine, acetonitrile, ethanol, chloroform, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, tetrahydrofuran, water and 3-methoxybutanol or a mixture thereof.
It is desirable to carry out the reaction in the presence of an acid receptor such as an inorganic base or an organic base, and its examples include an alkali metal or alkaline earth metal carbonate or bicarbonate or triethylamine, pyridine, 1,8-diazabicycloundecene, N,N-diisopropylethylamine or the like organic basic compound.
The reaction can be carried out generally at a temperature of from room temperature to 200xc2x0 C., preferably from 25 to 150xc2x0 C. The reaction is carried out for a period of from 30 minutes to 48 hours and completes generally after about 30 minutes to 2 hours.
As the protective group of an amino group, it may be any protective group generally used in this field, and its examples include tert-butoxycarbonyl group, 2,2,2-trichloroethoxycarbonyl group and the like (substituted) alkoxycarbonyl groups; benzyloxycarbonyl group, para-methoxybenzyloxycarbonyl group, para-nitrobenzyloxycarbonyl group and the like (substituted) aralkyloxycarbonyl groups; acetyl group, methoxyacetyl group, trifluoroacetyl group, chloroacetyl group, pivaloyl group, formyl group, benzoyl group and the like (substituted) acyl groups; tert-butyl group, benzyl group, para-nitrobenzyl group, para-methoxybenzyl group, triphenylmethyl group and the like (substituted) alkyl groups or (substituted) aralkyl groups; methoxymethyl group, tert-butoxymethyl group, tetrahydropyranyl group, 2,2,2-trichloroethoxymethyl group and the like (substituted) ethers; and trimethylsilyl group, isopropyldimethylsilyl group, tert-butyldimethylsilyl group, tribenzylsilyl group, tert-butyldiphenylsilyl group and the like (alkyl and/or aralkyl)-substituted silyl groups.
When each of Y and Y1 is an alkyl group having from 1 to 6 carbon atoms, an alkoxymethyl groups having from 2 to 7 carbon atoms or a phenylalkyl group composed of an alkylene group having from 1 to 6 carbon atoms and phenyl group, it can be converted into a corresponding carboxylic acid by treating it under an acidic or basic condition which is generally employed for the hydrolysis of carboxylic acid esters.
When Y1 is a structure of the formula (IV), its conversion into corresponding carboxylic acid can be effected by allowing the compound (III) or compound (V) to react with the compound (VI) and then treating it under an acidic or basic condition.
In addition, when de-protection is necessary, the compound of interest represented by the formula (I) can be obtained by removing the protective group under conditions suitable for the protective group.
The compound of formula (VI) can be produced by various methods, for example, it can be synthesized by a method shown in the reference examples as a preferred example, though not particularly limited thereto.
The compound of formula (VI) can be formed by removing Qxe2x80x2 from a compound represented by the following formula 
[wherein R222 is the same as the R2 defined in the formula (I) or represents a protective group of an amino grpup, R1, R3, R4, R5, R6, R7 and R8 are as defined in the formula (I), Qxe2x80x2 is a protective group of an amino group, wherein the protective group of an amino group may be selected from the group consisting of a (substituted) alkoxycarbonyl group, a (substituted) aralkyloxycarbonyl group, a (substituted) acyl group, a (substituted) alkyl group, a (substituted) aralkyl group and substituted silyl groups].
The compound described above can be present as a salt thereof, a hydrate thereof or a hydrate of the salt. As examples of the acid addition salt, an inorganic acid salt and an organic acid salt can be cited. Their illustrative examples include hydrochloride, sulfate, hydrobromide, hydroiodide, phosphate and the like inorganic acid salts, or methanesulfonate, benzenesulfonate, toluenesulfonate (sulfonic acid salts), acetate, citrate, maleate, fumarate, lactate (carboxylic acid salts) and the like organic acid salts.
When R222 and Qxe2x80x2 are protective groups of an amino group, they may be the same or different from each other, but it is convenient for producing the compound (I) that each is cut off under different reaction conditions.
As the R222 and Qxe2x80x2 which are protective groups of an amino group, the following can be exemplified. That is, they are a (substituted) alkoxycarbonyl group, a (substituted) aralkyloxycarbonyl group, a (substituted) acyl group, a (substituted) alkyl group, a (substituted) aralkyl group and substituted silyl groups.
The illustrative examples thereof include tert-butoxycarbonyl group, 2,2,2-trichloroethoxycarbonyl group and the like (substituted) alkoxycarbonyl groups; benzyloxycarbonyl group, para-methoxybenzyloxycarbonyl group, para-nitrobenzyloxycarbonyl group and the like (substituted) aralkyloxycarbonyl groups; acetyl group, methoxyacetyl group, trifluoroacetyl group, chloroacetyl group, pivaloyl group, formyl group, benzoyl group and the like (substituted) acyl groups; tert-butyl group, benzyl group, para-nitrobenzyl group, para-methoxybenzyl group, triphenylmethyl group and the like (substituted) alkyl groups or (substituted) aralkyl groups; methoxymethyl group, tert-butoxymethyl group, tetrahydropyranyl group, 2,2,2-trichloroethoxymethyl group and the like (substituted) ethers; and trimethylsilyl group, isopropyldimethylsilyl group, tert-butyldimethylsilyl group, tribenzylsilyl group, tert-butyldiphenylsilyl group and the like substituted silyl groups.
When the compound (I) is produced using the above compound having Qxe2x80x2 as a protective group, it is necessary to carry out the reaction by removing the protective group Qxe2x80x2. In that case, its reaction with the compound (III) or (V) may be carried out generally by one pot, or the reaction may be carried out after once isolating the compound (VI) by removing the protective group.
Cis-2-fluorocyclopropylamine comprised of a single isomer, which is desirable for the synthesis of the compound of formula (I) comprised of a single isomer, can be synthesized for example by the method described in JP-A-2-231475 (the term xe2x80x9cJP-Axe2x80x9d as used herein means an xe2x80x9cunexamined published Japanese patent applicationxe2x80x9d). Synthesis of the compound of formula (I) comprised of a single isomer using the optically active cis-2-fluorocyclopropylamine derivative obtained in this manner as the material can be carried out in accordance with the method described for example in JP-A-2-231475.
Since the compound of the invention has potent antibacterial actions, it can be used as medicaments for use in human bodies, animals and fishes or as preservatives of agricultural chemicals and food.
When the compound of the invention is used as a medicament for human bodies, its dose is within the range of from 50 mg to 1 g, preferably from 100 mg to 500 mg, per day per adult.
Also, its dose as animal use varies depending on the purpose of its administration (treatment or prevention), kind and size of each animal to be treated and kind and degree of each infected pathogenic bacterium, but is within the range of generally from 1 mg to 200 mg, preferably from 5 mg to 100 mg, per 1 kg body weight of each animal as a daily dose.
The daily dose is administered once a day or by dividing it into 2 to 4 doses per day. As occasion demands, the daily dose may exceed the aforementioned range.
Since the compound of the invention is active against a broad range of microorganisms which cause various infectious diseases, it can treat, prevent or alleviate diseases induced by these pathogens.
As bacteria or bacterioid microorganisms on which the compound of the invention is effective, the genus Staphylococcus, Streptococcus pyogens, hemolytic streptococci, enterococcus, pneumococcus, the genus Peptostreptococcus, Neisseria gonorrhoeae, Escherichia coli, the genera Citrobacter, the genus Shigella, Klebsiella pneumoniae, the genera Enterobacter, the genus Serratia, the genus Proteus, Pseudomonas aeruginosa, Haemophilus influenzae, the genus Acinetobacter, the genus Campylobacter, Chlamydia trachomatis and the like can be exemplified.
Also, as diseases which are induced by these pathogens, folliculitis, furuncle, carbuncle, erysipelas, phlegmon, lymphangitis, felon, subcutaneous abscess, hidradenitis, acne conglobata, infectious atheroma, perirectal abscess, mastitis, superficial secondary infections after injury, burn injury, operative wound and the like, pharyngitis, acute bronchitis, tonsilitis, chronic bronchitis, bronchiectasis, diffuse bronchiolitis, secondary infection of chronic respiratory disease, pneumonia, pyelonephritis, cystitis, prostatitis, epididymitis, gonococcal urethritis, nonspecific urethritis, cholecystitis, cholangitis, bacillary dysentery, enteritis, uterine adnexitis, intrauterine infection, bartholinitis, blepharitis, hordeolum, dacryocystitis, tarsadenitis, corneal ulcer, octitismedia, sinusitis, periodentitis, pericoronitis, jaw infection, peritonitis, endocarditis, sepsis, meningitis, skin infection and the like can be exemplified.
It is also effective against various microorganisms which cause infectious diseases in animals, such as the genus Escherichia, the genus Salmonella, the genus Pasteurella, the genus Haemophilus, the genus Bordetella, the genus Staphylococcus, the genus Mycoplasma and the like.
Illustrative examples of such diseases include colibacillosis, pullorum disease, avian paratyphoid, avian cholera, infectious coryza, staphylococcosis, mycoplasma infection and the like in the case of birds, colibacillosis, salmonellosis, pasteurellosis, haemophilus infection, atrophic rhinitis, exudative epidermis, mycoplasma infection and the like in the case of pigs, colibacillosis, salmonellosis, hemorrhagic sepsis, mycoplasma infection, bovine pleuropneumonia, bovine mastitis and the like in the case of cattle, colisepsis, salmonella infection, hemorrhagic sepsis, uterine empyema, cystitis and the like in the case of dogs, and exudative pleurisy, cystitis, chronic rhinitis, haemophilus infection, kitten diarrhea, mycoplasma infection and the like in the case of cats.
The antibacterial preparation which comprises the compound of the invention can be prepared by selecting an appropriate preparation depending on each administration method and employing generally used various preparation methods. Regarding the dosage form of the antibacterial preparation which uses the compound of the invention as its principal agent, tablets, powders, granules, capsules, solutions, syrups, elixirs, oily or aqueous suspensions and the like can be exemplified as oral preparations. Regarding injections, a stabilizing agent, an antiseptic agent and a solubilizing agent may be used in the preparation, or a solution which may contain these auxiliary agents may be contained in a container and made into a solid preparation by freeze-drying or the like means to be re-dissolved when used. In addition, a single dose may be contained in a single container or multiple doses may be contained in the same container.
Also, solutions, suspensions, emulsions, ointments, gels, creams, lotions, sprays and the like can be exemplified as preparations for external use.
Solid preparations may contain pharmaceutically acceptable additives together with the active compound and can be prepared for example by mixing the compound with additives optionally selected from fillers, extenders, binders, disintegrators, solubilization enhancing agents, moistening agents, lubricating agents and the like.
As liquid preparations, solutions, suspensions, emulsions and the like can be exemplified, which may contain a suspending agent, an emulsifying agent and the like as additives.
Examples of the method for administering the compound of the invention to animals include a method in which it is orally administered directly or by mixing it with feed, a method in which it is made into a solution and then orally administered directly or by mixing it with drinking water or feed and a method in which it is administered by injection. As the pharmaceutical preparations for use in the administration of the compound of the invention to animals, it can be made optionally into powders, fine subtilaes, soluble powders, syrups, solutions or injections making use of the techniques generally used in this field.
Formulation examples of the pharmaceutical preparations are shown below.
The following describes the invention based on inventive examples and reference examples, though the invention is not limited thereto.